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Abstract

A history of an increase in pulmonary mass was presented in the right upper lobe of
a 72-year-old male. The bronchial brushing cytology specimens contained many sheet-like
or three-dimensional clusters of malignant cells having small to medium-sized, uniform
oval to round, and hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm,
admixed with mitotic figures. A coarsely granular chromatin pattern was predominantly
noted. We first interpreted it as suspicious of malignancy, such as atypical carcinoid.
A right upper lobectomy was performed, and gross examination revealed a centrally
cavity-formed tumor lesion, containing asymmetrically thinned wall and looking grayish
to whitish, partly adjacent to the bronchiolar wall. On microscopic examination, the
tumor was predominantly composed of a solid proliferation of atypical epithelial cells
without apparent glandular or squamous differentiation, often arranged in an alveolar
growth pattern with peripheral palisading. Immunohistochemically, these atypical cells
are negative for all three neuroendocrine markers and thyroid transcription factor
1, whereas positive for 34βE12, p63 and S-100 protein. Therefore, we finally made
a diagnosis of basaloid carcinoma with cavity formation. We should be aware that,
owing to its characteristic features, cytopathologists might be able to raise basaloid
carcinoma of the lung as one of differential diagnoses, based on careful cytological
examination.

Virtual slides

Keywords:

Basaloid carcinoma; Lung; Cytology; Cavitation

Background

Although basaloid carcinoma (BC) of the lung is a rare subtype of nonsmall cell lung
cancer, one original paper described that up to 32% tumors were reclassified as BCs
among a large series of surgically resected lung cancers with retrospective review,
originally classified as poorly or undifferentiated carcinoma [1]. In 1975, Spencer first reported the histopathologic, immunohistochemical, ultrastructural,
and clinical features of BC of the lung [2]. Subsequently, this entity was established based on the following criteria, as previously
described by Brambilla et al. in 1992 [3]: (1) A solid lobular or anastomotic trabecular pattern growing invasively in a finger-like
fashion from the bronchial and/or glandular duct lining; (2) Small cuboidal to fusiform cells of mean diameter 12 to 15 μm, with moderately hyperchromatic
nuclei and without prominent nucleoli. There was a scant but visible cytoplasm, and
no nuclear molding; (3) Peripheral palisading with radially arranged cells at the periphery of lobules; (4) A high rate of mitosis, between 15 and 44 per 10 high-power fields. The World Health
Organization (WHO) classification of tumours of the lung now records carcinoma with
basaloid pattern, either as a pure BC, a variant of large cell carcinoma with above
typical histopathologic patterns, or as a basaloid variant of squamous cell carcinoma
when coexisted with areas of squamous differentiation [4]. BC of the lung often poses a diagnostic challenge to clinicians and cytopathologists,
since its entity is difficult to diagnose pre-operatively [5,6]. In fact, one old paper reported that the cytologic differentiation of BC extensively
overlap with those of small cell carcinoma [5]. Although another group demonstrated that patients with BC of the lung did not have
a poor prognosis than the other nonsmall cell lung cancers [7], Brambilla et al. recently have confirmed that lung carcinoma with a basaloid pattern is a unique entity
with a significantly worse outcome [8], similar to BCs in organs other than the lungs [3]. Thus, it would be critical to establish an accurate preoperative diagnosis by bronchial
brushing and washing cytology.

Indeed, pulmonary BC could be a relatively uncommon disease, but not as compared with
some recently published case reports of extremely rare tumor cell types in the lung
[9,10]. Despite of that, we report a unique surgical case of BC of the lung, associated
with central cavitation. Based on the cytology specimens, we preoperatively interpreted
it merely as suspicious of carcinoma.

Case presentation

The patient had a history of cerebral infarction 10 years ago. He was a heavy smoker
over 50 years. There was no history of malignancy, immunosuppressive disorders, use
of immunosuppressive medications, or unusual infections.

During a follow-up of his infarction, a chest X-ray showed a mass shadow with central
cavity area in the middle region of the right lung 1 and half years before the surgery.
The sputum culture examined detected colonies of Mycobacterium Gordonae, however,
following that, a recent increase of pulmonary mass was presented. Laboratory data,
including blood cell count and chemistry, were almost within normal limits, except
for high levels of blood urea nitrogen (BUN; 38 mg/dL) and creatinine (Cr; 1.87 mg/dL),
manifesting as mild renal dysfunction. Carcinoembryonic antigen (CEA; 4.3 ng/mL),
squamous cell carcinoma antigen (SCC; 5.3 ng/mL), cytokeratin 19 fragment (CYFRA;
5.3 ng/mL), neuron specific enolase (NSE; 13.5 ng/mL), and pro-gastrin-releasing peptide
(pro-GRP; 78.8 pg/mL) levels as tumor markers were modestly increased up, but carbohydrate
antigen (CA) 19–9 and sialyl Lewis X-i antigen (SLX) levels were within normal limits.
A chest CT scan revealed a relatively well-demarcated mass, measuring approximately
37 x 30 x 23 mm, associated with central and variably thin-walled cavity formation,
in the right upper lobe, S2. CT scans of the head and abdomen disclosed no definite
evidence of metastases in the lymph nodes or other organs. The patient had neither
recurrence nor metastases of the lung cancer, respectively, however, was dead due
to bronchopneumonia at 3 years after the operation.

Pathological findings

The first bronchial brushing cytology specimens were consisted of many clusters of
cohesive and sheet-like or three-dimensional tumor cells and a small number of individual
tumor cells without necrotic or hemorrhagic backgrounds (Figure 1A). The bronchial washing cytology specimens were relatively inadequate, but very similar
to the findings of brushing one. The malignant cells showed small to medium-sized
(12 to 20 μm in diameter), relatively uniform, and round to oval with mild pleomorphism
and had relatively scanty cytoplasm (Figure 1B). Additionally, the nuclei were hyperchromatic, predominantly in a coarsely granular
chromatin pattern, and often had inconspicuous nucleoli, but occasionally mitotic
figures (Figure 1B). Rosettes were absent, whereas a very small number of malignant squamoid cells was
rarely seen. Based on that, we first interpreted it as suspicious of carcinoma, such
as atypical carcinoid, and an ordinary right upper lobectomy was performed. On the
other hand, the transbronchial lung biopsy specimens from the pulmonary mass were
too small to be diagnostic.

Figure 1.Cytomorphologic examination of the bronchial brushing cytology specimens. (A) The cytology specimens were consisted of many clusters of cohesive and sheet-like
or three-dimensional tumor cells and a small number of individual tumor cells without
necrotic or hemorrhagic backgrounds (Papanicolaou stains). Bar = 25 μm. (B) Those malignant cells showed small to medium-sized (12 to 20 μm in diameter), relatively
uniform, and round to oval with mild pleomorphism and had relatively scanty cytoplasm.
Additionally, the nuclei were hyperchromatic, predominantly in a coarsely granular
chromatin pattern, and had inconspicuous nucleoli but mitotic figures (arrowhead)
(Papanicolaou stains). Rosettes were absent. Bar = 25 μm.

On gross examination, the cut surface revealed a centrally cavity-formed, relatively
poorly-demarcated, and solid firm mass, measuring 35 x 27 x 25 mm, which looked from
grayish to whitish in color, partially adjacent to the bronchiole (Figure 2A). This central cavity measured approximately 30 x 10 mm, but filled with no necrobiotic
materials. The background of the lung had no remarkable change, i.e., not emphysematous
(Figure 2A). A scanning magnification of it showed that the cancer components, less than 30%
in volume, were surrounded by the cavity and irregularly grew up along the asymmetrically
thickened but relatively thin cavity wall, together with extension to the peripheral
alveolar wall in a sheet-like fashion (Figure 2B). This tumor lesion was partly adjacent to the bronchiolo-vascular bundle (Figure
2B). These features might indicate a sequential progression from the bronchiole to the
surrounding alveolar space. There were no carcinoma in situ components within our thorough investigation.

Figure 2.Gross and microscopic examination of the resected specimen. (A) On gross examination, the cut surface revealed a centrally cavity-formed, relatively
poorly-demarcated, and solid firm mass, measuring 35 x 27 x 25 mm, which looked from
grayish to whitish in color, partially adjacent to the bronchiole (lower side, inset).
This central cavity measured approximately 30 x 10 mm, but filled with no necrobiotic
materials. Bar = 10 mm. (B) A scanning magnification of it (H&E stains) showed that the cancer components were
surrounded by the cavity and irregularly grew up along the asymmetrically thickened
but relatively thin cavity wall, together with extension to the peripheral alveolar
wall in a sheet-like fashion (lt. side). This tumor lesion was partly adjacent to
the bronchiolo-vascular bundle (rt. lower side). There were no carcinoma in situ components in our case. Bar = 5 mm.

Microscopic findings showed a solid and sheet-like proliferation of relatively uniform
and small to medium-sized atypical epithelial cells having hyperchromatic nuclei and
scant eosinophilic cytoplasm, often arranged in an alveolar fashion with peripheral
palisading, typical of BC of the lung (Figure 3A). By contrast, rosettes structures were absent. Apparent keratinization, intercellular
bridge, or glandular differentiation was also not evident, and there was not intracytoplasmic
mucin with Alcian-Blue staining. On high-power view, mitotic counts were high (more
than 15 per 2 mm2) (Figure 3B). The carcinoma cells partly involved the adjacent bronchiolar wall but without evidence
of vessel permeation. Moreover, although foci of comedo-type tumor necrosis were not
recognized within the cancer nests and the central cavity, the cancer-cavity junction
sometimes contained coagulative necrosis of pre-existing alveolar wall (Figure 3C). Immunohistochemically, these carcinoma cells were negative for all three neuroendocrine
markers, i.e., synaptophysin, chromogranin A and CD56, TTF-1, CEA, CK20, h-caldesmon,
α-SMA, calponin, and CD10, but specifically positive for 34βE12 (Figure 4A), CK7 and p63 (Figure 4B). Additionally, one part of tumor nests was positive for S-100 protein (Figure 4C). On the other hand, MIB-1 labeling index was approximately 5% in the proliferating
atypical cells of the cancer nests. All immunohistochemical profile of the carcinoma
cells is summarized in Table 2.

Figure 3.Microscopic examination of the BC of the lung. (A) Low power view showed a solid and sheet-like proliferation of relatively uniform
and small to medium-sized atypical epithelial cells having hyperchromatic nuclei and
scant eosinophilic cytoplasm, often arranged in an alveolar fashion with peripheral
palisading. However, rosettes structures were absent. Apparent keratinization, intercellular
bridge, or glandular differentiation was also not evident (H&E stains). Bar = 100
μm. (B) On high-power view, mitotic counts (arrowheads) were high (more than 15 per 2 mm2) (H&E stains). Bar = 25 μm. (C) Although foci of comedo-type tumor necrosis were not recognized within the cancer
nests and the central cavity, the cancer-cavity junction contained coagulative necrosis
of pre-existing alveolar wall (inset) (H&E stains). Bar = 1 mm.

Figure 4.Immunohistochemical examination of the BC of the lung. (A, B, C) The carcinoma cells of BC were specifically positive for 34βE12 (A) and p63 (B).
Additionally, one part of tumor nests was positive for S-100 protein (C). Bars = 50
μm.

Table 2.Immunohistochemical profile of the carcinoma components in our case of BC of the lung

Based on all these features, we suggested that these carcinoma cells were not characteristic
of neuroendocrine, squamous, glandular, or transitional differentiation, and finally
made a diagnosis of BC of the lung associated with central cavitation. Final pathological
stage was determined as pT2aN0M0, stage IB, according to the International Association
for Study of Lung Cancer (IASLC) classification [11].

Discussion

Unlike the current BC case, frequent carcinoma in situ components should cause advanced clinical treatment, including more aggressive surgery
or adjuvant chemotherapy, even in the early stage for BC of the lung [8]. It would lead to confer a significantly poor prognosis of BC amongst nonsmall cell
lung cancer in stage I to II patients [8]. Thus, it could be critical to establish an accurate preoperative diagnosis by bronchial
brushing and/or washing cytology, the clinical utility of which in diagnosing pulmonary
tumors has been generalized. The cytological characteristic of BC of the lung would
partly reflect the histopathological ones, showing cohesive, three-dimensional and/or
sheet-like clusters of relatively small and uniform malignant cells, often having
finely granular chromatin, inconspicuous nucleoli, high mitotic rate and scanty cytoplasm,
arranged occasionally in a rosette-like pattern, as well as single cells formation
in the background of possible necrosis [4-6]. However, in fact, the features of this relatively new and rare entity have not been
well described or reviewed more recently. As in the present case, the cytology findings
(Figure 1) showed almost similar to those as described above, even though neither rosette-like
fashion nor necrotic backgrounds were evident. In spite of that, a confident and accurate
diagnosis of BC of the lung might be impossible only on cytology specimens, likely
due to lack of experience, cytomorphologic variety, misinterpretation and/or sampling
errors. Nevertheless, in cases without evidence of neuroendocrine or squamous or glandular
differentiation, such as ours, cytopathologists should raise possibility of BC as
one of differential diagnoses, other than large cell neuroendocrine carcinoma, atypical
carcinoid, small cell carcinoma, poorly differentiated squamous cell carcinoma or
adenocarcinoma, or basaloid variant of squamous cell carcinoma, at the very least.
Future studies will be further required after collecting and examining a larger number
of pulmonary BC cases.

It is very likely that our case report is histopathologically remarkable for two reasons
at least: first, central cavitation accompanied uniquely within the tissue of BC (Figure
2). Actually, to date, the number of ‘true’ cases reported as BC of the lung in the
English literatures is not large, and most recent reference is from 2008 within our
thorough investigation [8]. According to those papers, all BC tumors have exhibited nodular or mass lesions
without cavity formation, not similar to our case. Furthermore, this case peculiarly
showed coagulative necrotic foci of pre-existing alveolar wall in the cancer-cavity
junction (Figure 3C), indicating ischemic change of the pulmonary tissue surrounded by the BC areas.
Xue et al. have very recently proposed that the solitary thin-walled cavity of lung adenocarcinoma
would be formed via multiple processes: adenocarcinoma cells initially develop in
alveolar wall and grow toward bronchiole, and next formed a unidirectional check-valve
owing to lack of cartilage in bronchiole; the accumulations of gases enter alveoli;
the alveoli rupture and fuse into cavity with separation; and finally, the cavity
gradually gets larger and larger with the increased inner pressure [12]. As in our BC case, it was suggested that the carcinoma cells firstly developed in
the bronchiolar wall and subsequently grew extensively toward alveolar wall, and vice versa, since BC of the lung could originate from a basal bronchial or bronchiolar epithelial
stem cell, as described by Brambilla et al.[3]. In this scenario, the above peculiar histopathological findings (Figure 3C) might confirm their above hypotheses with regard to the pathogenetic mechanisms
of solitary thin-walled cavitation in lung cancer [12]. It would be intriguing to study this topic after investigating many cases of it.
Second, immunohistochemical expression of not merely p63 but S-100 protein was positively
seen in the tumor nests (Figure 4). Although there have been no large, detailed immunohistochemical studies of BC of
the lung until now, the results indicate that those tumor cells have potential myoepithelial
phenotypes, as well. We could provide the possible evidence for the first time that
BC of the lung might arise from a ductal epithelial-myoepithelial cell, as a result
of neoplastic transformation of outer supporting myoepithelial cells, as well as inner
ductal epithelial cells [13]. However, since other myoepithelial markers examined, such as α-SMA, calponin, and
CD10, were negative (Table 2), this suggestion may be highly speculative and partly unsupported. Despite of that,
future convincing data will be further required to determine whether our hypothesis
is significant or not.

Conclusion

We herein reported a rare case of BC of the lung associated with central cavitation.
The present case was tentatively diagnosed as suspicious of carcinoma, not otherwise
specified, on the cytology specimens, since its features showed unclear differentiation.
All cytopathologists should be aware that its cytomorphologically characteristic findings
from extensively careful examination might induce one of differential diagnoses, and
possibly a correct diagnosis. BC of the lung may be more common than generally considered.

Consent

Written informed consent was obtained from the patient for publication of this case
report and any accompanying images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SY and HN participated in conception of the idea and writing of the manuscript. SY,
HN, TT, AN, SK, TB, HU, TH and YS performed the cytohistological and immunohistochemical
interpretation of the tumor tissue. All authors have read and approved the final manuscript.